In many instances, the suppression of biosynthesis of sterols is desirable. For example, it is often desirable to suppress the formation of the sterol cholesterol in animals, including humans, whereby the serum cholesterol level in the animal will be lowered.
The concentration of cholesterol in blood serum has been correlated with a number of diseases, particularly atherosclerosis. Atherosclerosis is a condition marked by the formation of plaques in the arterial system. Cholesterol and cholesterol esters are major components of these plaques. While the etiology of the disease is not completely known, it appears that an elevated serum cholesterol level contributes to the development and the progression of atherosclerosis.
Cholesterol in animals is derived from two sources, first the intake and absorption of dietary cholesterol and second the biosynthesis of cholesterol from acetate by cells of various organs of the body, e.g., liver, intestines, and skin. The biosynthesis of cholesterol and other sterols from acetate in the body involves a complex sequence of reactions, one of which is the conversion of 3-hydroxy-3-methylglutaryl Coenzyme A into mevalonic acid. This reaction is considered to be a major regulation point in the normal biosynthesis of cholesterol in cells. If the biosynthesis of mevalonic acid can be inhibited in vivo, production of sterols is reduced, and serum cholesterol levels can thereby be lowered.
In British Pat. No. 860,303 certain aryloxy carboxylic acid esters, such as the methyl ester of 2-(4'-chloro-phenoxy)isobutyric acid, are proposed for use in suppressing blood cholesterol levels. While this compound has acquired significant importance in the clinical treatment of humans, for various reasons it is not as effective as is desired. Accordingly, more effective compounds for suppressing serum cholesterol levels are of great interest and importance.
Obesity is also a serious health problem. The correlation between excess weight and a number of diseases, particularly cardiovascular diseases, is well-known. Many people, often for psychological or other reasons, find it difficult or impossible to adhere to weight control or weight loss diets. For this reason, techniques for safely and effectively suppressing appetite are greatly needed.
It is known from U.S. Pat. No. 4,202,891, which patent is fully incorporated herein, that certain 15-oxygenated sterols are effective in the inhibition of the biosynthesis of mevalonic acid and of sterols. A number of desirable effects can be derived from the inhibition of the biosynthesis of mevalonic acid, including suppressing the formation of cholesterol in animals, whereby serum cholesterol levels may be lowered.
In addition, the growth and proliferation of the cells of higher organisms and certain microorganisms, such as yeast and fungi, involve the formation of sterols. Accordingly, inhibition of the biosynthesis of mevalonic acid, and thus reducing sterol formation, is effective to inhibit the growth of cells, both normal and tumorous. Furthermore, inhibition of the biological synthesis of sterols has the effect of inhibiting the growth of certain microorganisms, thereby combatting fungal and yeast infections.
In addition to its role in sterol biosynthesis, mevalonic acid is an important percursor of a number of other important constituents of cells. Thus, while bacteria are generally considered to not contain or need sterols, their growth and proliferation requires synthesis of mevalonic acid and the products derived therefrom. Accordingly, inhibition of mevalonic acid biosynthesis should inhibit bacterial growth.
Also the 15-oxygenated sterols and their derivatives are effective to suppress appetite. While the mechanism by which the 15-oxygenated sterols function to suppress appetite is not known, it is believed that this effect is in some way related to the mevalonic acid or sterol biosynthesis inhibiting activity of the 15-oxygenated sterols.
The 15-oxygenated sterols of U.S. Pat. No. 4,202,891 represent desirable compounds that exhibit a high degree of activity. However, the heretofore known processes for manufacturing the 15-oxygenated sterols have proven costly and time consuming. Often very small yields of the desired products have been obtained or the processes proved difficult to carry out on a large scale for various reasons such as requirements for extensive chromatography. In addition, known processes for the production of 3.beta.-benzoyloxy-5-cholesta-7,14-diene, a key intermediate in the production of 15-oxygenated sterols from 7-dehydrocholesterol, have been unsatisfactory because known procedures are highly variable. On occasion the desired product was obtained in reasonable yield with a reasonable degree of purity; however, frequently the yield and purity were much lower than desired and unknown side products were observed.
The present invention provides a procedure for production, on a large scale, of high quality 15-oxygenated sterols in consistent high yields. Such a procedure, of course, provides corresponding effectiveness and efficiency.